Gabapentin is a drug that since 1993 is used for the adjuvant treatment of epilepsy. In 1998, two double-blind, randomized controlled trials suggested that gabapentin had mild analgesic effects on pain caused by diabetic peripheral neuropathy and postherpetic neuralgia. Subsequently, the use of gabapentin appeared for unapproved indications of pain treatment, migraine and even as a mood stabilizer.
In this way, the promotion of indications for the pain treatment by gabapentin was supported by the publication and selective citation of studies with favorable results, extending its application to neuropathic pain, gradually becoming the most durable market for the use of gabapentin, reinforced by the practice guidelines that referred to gabapentin as the first line of treatment. (Evidence: Update in Ambulatory Practice, April/June 2010. Vol. 13 No. 2).
Gabapentin is probably the most studied drug in its basic and clinical aspects, in order to elucidate its mechanism of action and establish its real clinical efficacy. It has been postulated that gabapentin exerts its effects through three different mechanisms: the facilitation of gabaergic transmission, the decrease in gabaergic transmission, the decrease of various ion channels. However, the available evidence on how gabapentin acts on such pathways is variable and often contradictory.
Gabapentin is an analogue of gamma-aminobutyric acid (GABA), it has been described that gabapentin is an agonist of the GABAB gb1a-gb2 heterodimer that is coupled to a subtype of potassium channel called Kir 3,1/3,2 (internal rectification of potassium channels). The consequence of this action of gabapentin would be a nervous hyperpolarization with a decrease in bioelectric activity. It has also been shown that gabapentin increases the cerebral content of GABA acutely and chronically, probably through the non-vesicular release of this neurotransmitter. (Baños J E, Malouf J., 2002).
A second possibility is that gabapentin acts by preventing the activation of glutamate receptors, especially NMDA, by direct or indirect actions. These receptors are complex structures and, for example, can be acted pharmacologically on the binding site of the agonist (glutamate), the associated ion channel or the binding site of glycine. Gabapentin does not act on the first two, but there are some indirect studies that indicate that it could do so on the third, since its effects are reversed by the D-serine administration, an agonist at the glycine binding site. The result would be a decrease in the activation of such receptors by glutamate. Additionally, electrophysiological studies have shown how gabapentin can even reduce the release of glutamate in the posterior horn of the spinal cord.
Perhaps, the most peculiar mechanism of action of gabapentin is the binding to a specific site, the α2δ subunit, present in all the voltage-dependent calcium channels (CCDV) that have been studied until today. The physiological role of this subunit is to increase the functional expression of calcium channel complexes. At present, three distinct subunits have been characterized, called α2δ-1, α2δ-2 and α2δ-3, but gabapentin binds only to the first two, especially at α2δ-1. Thus, by attaching to the α2δ subunit, gabapentin blocks the calcium entry through the presynaptic calcium channels, especially P and Q, but also L. In this way, the neurotransmitter release in various areas of the central nervous system would be inhibited.
Pain is defined as an unpleasant sensory and emotional experience associated with real or potential tissue injury, becoming the most frequent clinical manifestation.
The pharmacological treatments for pain described in the state of the art are integrated by three categories of medications: non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics and adjuvant analgesics.
Among the main NSAIDs are: acetaminophen, lysine acetylsalicylate, acetylsalicylic acid, mefenamic acid, diclofenac, etodolac, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, sulindac, among others.
Opioid analgesics act on opioid receptors located in the Central Nervous System and in the spinal cord by inhibiting the adenylyl cyclase enzyme, reducing the amount of intracellular cAMP. They open the K+ ion channels and inhibit the Ca2+ channels. Among the main opioid analgesics are: anilinopiperidine, diphenylmethane, phenylpiperidine, oripavine, morphinan, among others.
Adjuvant analgesics are those whose main pharmacological action is not analgesia, however, they are generally used in a complementary way to the pain treatment to increase the analgesic effect of other drugs, decreasing their toxicity, the requirements of opiates, improving pain associated symptoms, fighting adverse effects of analgesics, allowing pain relief and concomitant psychological disorders. Gabapentin and caffeine are among the adjuvant analgesics useful for the pain treatment effectively.
The pain treatment in animals by the veterinarian is not only an ethical and humanitarian practice, but also based on limiting the serious physiopathological consequences derived from a painful stimulus. It is known that untreated pain causes distress, prolongs the recovery and hospitalization time, hinders the healing process, can lead to self-mutilations, causes hypoxia/hypercarbia, increases cellular catabolism, produces neuronal sensitization and, ultimately, increases the morbidity and mortality of patients.
Both narcotic analgesics (opioids) and NSAIDs are very effective in treating perioperative pain of moderate to severe intensity, however, one of the problems when using NSAIDs in animals is that there is a likelihood that they will suffer some type of poisoning.
In the case of paracetamol the recommended dose for dogs is 15 mg/kg/8 h, the toxic dose in cats 50 mg/kg and in dogs 150 mg/kg. Cats have very low levels of glucuronyl transferase and limited activity to conjugate sulfates, which oxidized by CP450 give rise to a toxic metabolite: N-acetyl-para-benzoquinoneimine (NAPQ). This compound, covalently linked with macromolecules, is involved in the hemoglobin transformation to methaemoglobin, forming Heinz bodies, increasing the osmotic fragility of erythrocytes, and leading to hemolysis, anemia and, particularly, cats are especially sensitive to acute renal failure.
In the case of acetylsalicylic acid, the therapeutic and toxic doses are very close, being the anti-inflammatory dose of 25 mg/kg/8 h and the analgesic of 10-20 mg/kg/8 h in dogs. In this species, vomiting and gastric ulcers have been described due to the intake of doses greater than 50 mg/kg/24 h and 100 mg/kg/24 h for 1 and 4 weeks respectively. Cats have a defect in the activity of the glucuronosyl transferase enzyme, so they are more susceptible to poisoning. The analgesic and toxic doses in this species are 10 mg/Kg/48 h, and 80-120 mg/Kg/24 h for 10 and 12 days respectively. The product is absorbed at the gastric and intestinal level, undergoes hepatic metabolism and is excreted via the kidneys, it is bound by 90% to plasma proteins.
Clinical condition is mainly due to the inhibition of prostaglandins, causing effects at digestive, platelet and renal levels. The acute condition occurs 4-6 hours after ingestion. It is characterized by depression, anorexia, hyperthermia, hyperglycemia and glycosuria, vomiting, hematemesis and tachypnea (because salicylates increase oxygen consumption, CO2 production at striated muscle level and stimulate the respiratory center of the bulb). This situation can lead to an alteration of the acid-base state, and finally lead to acute renal failure, weakness, coma and non-cardiogenic pulmonary edema. The chronic condition is characterized by gastric ulcers with or without perforation, toxic hepatitis, anemia and delay in bleeding times, due to inhibition of the bone marrow. In cats, nausea and vomiting, respiratory depression and metabolic acidosis, hyperthermia, seizures and coma, toxic hepatitis, Heinz body anemia and thrombocytopenia are observed. Hypernatremia and hypokalemia can also be observed (Daza M A, 2004).
The use of phenylbutazone in horses for the claudication treatment (2 g/12 h/IV for 8 days) has caused gastric ulcers and necrotizing colitis with protein loss.
NSAIDs cause nephropathy by inhibiting the synthesis of vasopressor prostaglandins that regulate renal blood flow, glomerular filtration, tubular ion transport, renin release, and water metabolism.
The gastric and intestinal lesions caused by phenylbutazone are the result of microvascular injury and the decrease in mucus production due to low concentrations of prostaglandins. By inhibiting the metabolic pathway of arachidonic acid by cyclooxygenase blocking, the lipoxygenase pathway is increased, which increases the leukotrienes, hydroperoxy-eicosatetraenoic acids and free radicals which in turn are also gastrolesive. (Amaya, 2011)
In patent documents WO99/12537 and WO2000053225 refer to the combination of naproxen with gabapentin, integrating studies in rats by parenteral administration.
In the state of the art, it was found that the patent MX223993 refers to the use of pregabalin or gabapentin for the pain treatment, however, said document and the commercialized products derived from it, are focused on the pain treatment in humans, managing therapeutically required doses specific for humans. On the other hand, the patent application WO2006123247 refers to a combination for veterinary use comprising the combination of gabapentin and/or pregabalin with carprofen for the pain treatment and/or inflammation, especially in dogs, cats and horses. This patent application describes the oral dosage forms, indicating various excipients, however it does not specify any formula suitable for oral administration specific for animals, besides that the tests of the drug combination is carried out by parenteral administration.
In this way, the administration of combinations of two or more NSAIDs, or together with corticosteroids, potentially increases their toxicity. Besides this, the ignorance of the condition of liver or kidney functionality of pets, the treatment with NSAIDs is highly dangerous, however, these drugs are commonly used by veterinarians or animal owners.
Meanwhile, the use of gabapentin for the pain treatment and epilepsy has been focused on human use, even though all the studies have been carried out on animals (mainly rodents), little has been reported about its veterinary application orally and there are no compositions that provide safety and effectiveness when administered in animals, such as pets.
It is necessary to have compositions that, in addition to being stable, preserve efficacy after oral administration, that is, that allow the control of pain or epileptic events in pet animals without presenting the toxic effects that NSAIDs can produce.
Likewise, there is a need to administer different doses, according to the variety of size and weight of the companion animals, so, the segmentation of the tablets is the most viable option because they allow adjustments in the medication dose, easier swallowing and cost savings for both the owner of the animal and health providers.
However, during the manufacturing process the segmentation of the tablet presents drawbacks, since it can be difficult to carry out due to its hardness, the segments obtained are usually of different size, an amount can be lost during the segmentation (Verrue, 2010) so that the homogeneous distribution of the active principle of each segment can be questionable.
However, conduction of relevant analyzes such as assessment, hardness and bioavailability allow demonstrating that said drawbacks will not occur and each segment obtained from the tablet will have the same physical, chemical and therapeutic characteristics.